The search for strong analgesics which also possess minimal potential for dependency has been among the highest priority efforts in pharmaceutical research. These research efforts have, to a great extent, involved chemical modification of the opiate structure and the discovery of novel compounds which possess morphine-like activity.
The concept of multiple opioid receptors has been supported by studies with nalorphine and a series of benzomorphans which display unusual pharmacological properties dissimilar from morphine, yet blocked by the opioid antagonists. [See, for example, W. R. Martin, et al., J. Pharmacol. Exp. Ther., 197: 517-532 (1976).]
The existence of multiple types of opioid receptors is of importance because it suggests the possibility of separating the desirable analgesic and psychotherapeutic effects of a drug compound from the undesirable abuse potential or habituating effects.
U.S. Pat. No. 4,098,904 discloses certain cis- and trans-N-(2-aminocycloaliphatic) benzamide compounds having analgesic activity.
U.S. Pat. No. 4,145,435 describes certain 2-amino-cycloaliphatic amide compounds as analgesics. In particular, trans-3,4-dichloro-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzeneacetami de is reported to possess selective kappa agonist activity, and therefore, to possess analgesic activity without attendant dependence liability. [See P. V. Vonvoigtlander, et al., J. Pharmacol Exp. Ther., 224: 7-12 (1983).]
U.S. Pat. No. 4,212,878 discloses certain N-[(4-mono- or di-oxygen-group-substituted-1-aminocyclohex-1-yl)methyl]benzeneacetamides, particularly 2-(3,4-dichlorophenyl)-N-[[8-(1-pyrrolidinyl)-1,4-dioxaspiro[4.5]dec-8-yl] methyl]acetamide having analgesic properties.
U.S. Pat. No. 4,359,476 and its continuation-in-part 4,460,600 disclose certain N-[2-amino(oxy or thio group) substituted cycloaliphatic]benzeneacetamide and -benzamide compounds having the oxy- or thio group substituents on a cycloaliphatic ring carbon adjacent to either of the nitrogen-bearing carbon atoms of the cycloaliphatic ring. These compounds, having analgesic activity are typified by 4-bromo-N-[3-methoxy-2-(1-pyrrolidinyl)cyclohexyl]-N-methylbenzamide.
U.S. Pat. No. 4,598,087 and its divisional, U.S. Pat. No. 4,677,122, disclose certain oxy- or thioacetamides of trans-1,2-diaminocyclohexane having analgesic activity. These compounds are typified by trans-2-(2,3-dichlorophenoxy -N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]acetamide.
U.S. Pat. No. 4,656,182 discloses certain trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]benzo[b]thiophene acetamides having analgesic activity.
U.S. Pat. No. 4,663,343 discloses certain trans-N-methyl-N-[2-(1-pyrrolidinyl)cyclohexyl]naphthalenyloxy- and naphthalenylthioacetamides having analgesic activity.
U.S. Pat. No. 4,737,493 discloses certain substituted phenoxy-, 1-, and 2-naphthalenyloxy, indenyl-, indolyl-, benzofuranyl-, and benzo[b]thiophenylcarboxamides of 7,8-(substituted-diamino)-1-oxaspiro[4.5]decanes useful as analgesic agents.
U.S. Pat. No. 4,463,013 discloses certain oxygen substituted amino-cyclohexyl-benzeneacetamides as diuretics.
U.S. Pat. No. 4,438,130 discloses certain mono-oxa-, thiaspiro-cyclic-benzeneacetamide and benzamide compounds useful as analgesics.